This study represents a continuous effort to elucidate ischemic pathophysiologic mechanisms which could be involved in the tissue damage but at the same time provide clues for a single or multifactorial approach to prevent and/or treat this disease. These investigations were concerned with studying the cerebral regional turnover of dopamine (DA) and free radical membrane disturbances in ischemia and postischemia. Marked DA release, decrease of monoamine oxidase-derived metabolites (3,4-dihydroxyphenylaceytic acid and homovanillic acid), and accumulation of 3-methoxytyramine during ischemia and the first 15 min of reperfusion were greatly potentiated by pargyline pretreatment. Changes in the contents of dopamine and its metabolites, as well as in the increase in superoxide radical production, decrease of superoxide dismutase activity, and thiobarbituric acid-reactive material accumulation were more pronounced in the striatum than in the cortex. The ischemic release of dopamine is followed by a shift of dopamine metabolism toward production of 3-methoxytyramine during reperfusion due to inhibition of monoamine oxidase was confirmed by pargyline pretreatment. The observed imbalance between superoxide anion/superoxide dismutase ratio and accumulation of thiobarbituric acid-reactive material support the contention that inhibition of dopamine clearance from the extracellular space during reperfusion may contribute to the increased free radical formation and membrane damage in DA-rich regions such as the striatum.